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Fat and Cholesterol
Metabolism
www.taste.com.au
Dietary Fat
• Lipogenesis is not very active in people on a
Western diet
– Lipogenic enzyme expression is down-regulated
by fat consumption
– Most of our fat comes from the diet ~100g/day
– Most fat in white adipose tissue will have come from dietary
fat and not de novo lipogenesis
• Fat is hydrophobic
– Problems for digestion and transport
– Digestive enzymes need fat to be in an emulsion
– Fat needs to be carried around the bloodstream
within lipoproteins
Formation of Emulsions
• Molecules have hydrophilic and
hydrophobic characteristics
– amphiphilic
– amphipathic
• Phospholipids in cell membranes
– As is the phosphatidic acid and
lysolecithin in salad dressing
• Amphiphilic molecules act as
detergents
– emulsify fat into tiny ‘particles’
– micelles
Bilayers and Micelles
• In both structures, polar heads are facing the
aqueous environment while the hydrophobic tails
are buried in the core
• Micelles can also be formed using bile salts
Fat Digestion
• Fat is contained in the core of micelles that formed
with bile salts
• Churning of dietary fat with bile salts in the intestine
– Chyme
– Emulsion
– Easy for lipase to interact with
• Pancreatic Lipase
– Hydrolyses fat into FA and glycerol
– Plus mixture of mono- and di-acyl glycerols
Bile Salts
• Produced in the liver
• Made from cholesterol
– Cholesterol itself it not amphiphilic enough to be a
detergent - needs modification by addition of polar
groups
• Stored in the gall bladder
• After digestion of fat
– Reabsorbed and taken back to the liver
– Via hepatic portal vein
Bile Salts
• Polar groups are added to cholesterol to make it more
amphiphilic
• The only way to get rid of cholesterol is to make them into
bile salts (chol cannot be oxidised)
Undigested Fat
• If gall bladder is blocked by gall stones
– no bile salts secreted  less fat digestion  lower
calorie intake
• Inhibitors of fat digestion as weight-loss drugs
– Orlistat (brand name Xenical)
– Listed side effects include
• oily spotting; orange colored oil in your stool;
• gas with oily discharge;
• an urgent need to go to the bathroom; an inability to control
bowel movements, an increased number of bowel
movements.
Olestra
• Olestra (Olean) is a fat substitute
– FA attached to sucrose
– Not attacked by lipases
• Olestra will passes through gut undigested
– Carries with it fat soluble vitamins
• D, E, K need to be added as supplements
– See anti-Olestra sites
– eg. www.cspinet.org/olestra/
Lipoproteins
•
•
•
Mixture of phospholipid and Apoproteins
– Apoproteins role - Enzymes, Structural, Docking
Different types of lipoproteins characterised by size and by types of
apoproteins
First lipoproteins made by intestinal cells
– Chylomicrons
– Enter lymphatic system
•
Contains fat and cholesterol esters
Delivery of Fat to Tissues
Chylomicrons interact
with tissues through
lipoprotein lipase (LPL)
LPL is on the surface of
cells
Fat in chylomicrons
hydrolysed to fatty
acids and glycerol
Insulin stimulates LPL
Also increases the supply
of glycerol 3-phosphate
for re-esterification
Fate of FAs and Chylomicrons
• Fatty acids from chylomicron after lipolysis can be:
– Burnt in the heart and muscle
– Stored in WAT (hopefully not elsewhere)
• Build up of fat in the muscle associated with Type 2 diabetes
• FAs in WAT mainly re-esterified  FAT
– Re-esterification needs glycerol phosphate (Glyc3P)
– Glyc3P is made by glycolysis & glyceroneogenesis
• As fatty acids stripped out, chylomicron gets smaller
– And more cholesterol rich
– Form chylomicron remnants
Liver: Import/Export
Chylomicron remnants taken
up by liver
Endocytotic process
Internal digestion of remnants
Release of cholesterol into liver
Liver assembles VLDL from
fat and cholesterol esters
The fat could have been
made by lipogenesis
VLDL excreted into the
blood stream
VLDL & LDL - Transport of Cholesterol
LPL in peripheral tissues works on
VLDL just as it did on chylomicrons
 VLDL becomes fat depleted
Remaining particle (LDL) relatively
cholesterol rich
Tissues take up LDL through LDL
receptor
Endocytotic process like chylomicron
remnants.
This is how cholesterol is delivered to
the tissues
LDL Receptors
• Tissues express LDL receptors ONLY if want cholesterol
• Nearly all of our cells can make cholesterol themselves
–  when cells have enough cholesterol, they will stop
making cholesterol & stop expressing LDL receptor
• Macrophages take up LDL without control
–  produce foam cells  form plaques
• HMG-CoA reductase is the rate limiting step in making cholesterol
– Can be inhibited by statins
Reverse Cholesterol Transport
Ways to Reduce Blood Cholesterol
• Reduce consumption of cholesterol
– Less meat, dairy products
– But intake of cholesterol is very small vs stores
• Inhibit absorption of cholesterol from gut
– Phytosterols as competitive inhibitors?
•  reabsorption of bile salts by using resins that bind to
bile salts
– liver has to make more bile salts from cholesterol
• Inhibit cholesterol synthesis by using “statins” which
inhibit HMG-CoA reductase
• Consume polyunsaturated fatty acids
– high saturated fat results in  HDL and LDL
Cholesterol Flux
• Total cholesterol in body ~140g
• ~1g of cholesterol enters the body each day from diet
– But only 0.5 g absorbed
• ~18g bile salts secreted into gut per day
– and 17.5g is reabsorbed per day
– the net loss of bile salt is very little (~0.5 g/day)
• So amount absorbed = amount lost as bile salts
– A reduction in intake will most likely be met by an increase in
endogeous choleseterol synthesis
• But compare the store size to the intake
– 140 g to 0.5 g
– vs carbohydrate for which the store size and intake are similar
magnitude
– vs fat – intake (100 g) < store (15,000 g)
Importance of Cholesterol
• Cholesterol is important for:
– Steroid hormone synthesis
– Regulating membrane fluidity
• Membrane fluidity is important for:
– Structural integrity
– Receptor/enzyme activity
Membrane with Saturated FA
• saturated  FA
– No double bond in FA
• Membrane crystalline
Membrane with Unsaturated FA
• Unsaturated FA  Kinks
• Membrane is less crystalline, more fluid and
more permeable
Cholesterol & Membrane Fluidity
• Cholesterol “fine tunes” membrane fluidity